Topoisomerases are vital nuclear enzymes which function to resolve topological dilemmas in DNA, such as overwinding, underwinding and catenation, which normally arise during replication, transcription and perhaps other DNA processes. These enzymes allow DNA to relax by forming enzyme-bridged strand breaks that act as transient gates or pivotal points for the passage of other DNA strands. Topoisomerase-targeting drugs appear to interfere with this breakage-reunion reaction of DNA topoisomerases. In the presence of topoisomerase active agents an aborted reaction intermediate, termed a ‘cleavable complex’, accumulates and results in replication/transcription arrest, which ultimately leads to cell death.
The development of topoisomerase I (topo I) active agents therefore offers a new approach to the multi-regimental arsenal of therapies currently used in the clinic for the treatment of cancer. A recent article [Cancer Chemother. Pharmacol 1994, 34 (suppl), S41-S45] discusses topoisomerase I active compounds that are in clinical studies and these have been found to be effective clinical antitumor agents. These clinical candidates are structurally related to the alkaloid camptothecin (1). Other reports dealing with camptothecin analogs (Cancer Commun. 1990, 2, 395; Farm. Clin. 1997, 14, 250, 253, 256-258) have suggested a correlation between selective topoisomerase I inhibiting properties and potent antineoplastic activity in a variety of human tumors. In addition, certain cell lines which overexpress human topoisomerase I, including human colon carcinoma cells, have been demonstrated to be hypersensitive to camptothecin (Cancer Research 1992, 52, 525). 
A recent review highlights some of the non camptothecin topoisomerase I active agents (Expert Opin. Ther. Pat. 10:635-666, 2000). Further, indolo[2,3-a]carbazole derivatives related to the Rebeccamycin class, such as NB-506, are disclosed (EP Appl. 0 545 195 B1 and 0,602,597 A2; Cancer Research 1993, 53, 490-494; ibid 1995, 55, 1310-1315) and claimed to exhibit antitumor activity. However, unlike camptothecin which acts as a selective topo I poison, these derivatives have been reported to be non-selective, exhibiting additional biological effects, such as DNA intercalation (Cancer Research 1995, 55, 1310), tyrosine kinase activity (Molecular Pharmacol. 1999, 56, 185-195) and topoisomerase II activity (Proc. AACR 1997, 38, 75). Indolo[2,3-a]carbazole alkaloids such as rebeccamycin (U.S. Pat. Nos. 4,487,925 and 4,552,842) and its water-soluble, clinically-active analog, 6-(2-diethylaminoethyl)rebeccamycin (U.S. Pat. No. 4,785,085), are useful antitumor agents which target DNA. Related indolocarbazoles are also disclosed (WO 9530682) and claimed to exhibit antitumor activity.
Furthermore, fluoroindolocarbazoles such as those described in WO 98/07433 are antineoplastic agents with topoisomerase I inhibitory activity. U.S. Pat. No. 5,468,849 discloses certain fluororebeccamycin analogs as useful antitumor agents, along with a process for their production by fluorotryptophan analog feeding of a rebeccamycin-producing strain of Saccharothrix aerocolonigenes, preferably Saccharothrix aerocolonigenes C38,383-RK2 (ATCC 39243).
More recently Prudhomme, et al. report a series of indolocarbazoles derived from rebeccamycin which all display a so-called resistance index below 20 (Current Medicinal Chemistry 2000, 7, 1189). The resistance index was defined as IC50 P388CPT5/IC50 P388, where these IC50's are measures of the antiproliferative activities against murine P388CPT5 leukemia cells resistant to camptothecin and parental P388 cells, respectively.
Despite these examples, there remains a need for novel and potent cytotoxic compounds useful for selectively inhibiting topoisomerase I activity, thereby being useful as anti-cancer agents.